{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:03:49Z","timestamp":1773446629921,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Despite the wealth of information on biomarkers of diabetes complications in adults with type 1 diabetes, data in the pediatric population is limited. Diabetic nephropathy (DN), the leading cause of mortality in type 1 diabetes T1D), could be potentially missed in youth, as albuminuria, the current \u201cgold\u201d standard, may be transient and may not reflect permanent renal impairment. Soluble alpha KL has emerged as a potential marker of early diabetic nephropathy. Seventy-nine pediatric patients with type 1 diabetes meeting ISPAD criteria for nephropathy screening were consecutively recruited (90% Caucasian, 51% male, mean age 16.1 \u00b1 3.1 years, duration of T1D 7.2 \u00b1 3.9 years, 2-year average HbA1c 8.0 \u00b1 1.3%, and serum and urine samples were collected for analysis. Serum Klotho (KL) and circulating miRNA levels of select miRNA involved in the pathogenesis of DN were estimated. KL had a strong inverse correlation with diabetes duration and HbA1c, two important risk factors in the development of diabetes complications. Serum miR-192 were negatively associated with KL among children with prolonged duration of diabetes (\u226512 years) after adjustment for age and sex. In cell culture, overexpression of miR-192 significantly downregulated KL mRNA and protein levels, and reduced KL levels in the media. miR-192 mimic reduced luciferase activity in a reporter containing the KL 3\u2019 UTR (60% compared to controls, p&amp;lt;0.01), and the inhibitor rescued it. Deletion of a potential binding site for miR-192 in the KL 3\u2019UTR completely abolished the effect of miR-192 in the reporter assay, suggesting that KL is a direct target gene of miR-192. Overexpression of miR-192 significantly increased oxidative stress (MDA) and expression of inflammatory and senescence markers IL-6 and p16. Inhibition of miR-192 significantly reduced levels of MDA, IL-6 and p16. In summary, we demonstrate an increase in miR-192 and a decrease in KL levels in children with prolonged duration of T1D. We demonstrate a novel role for miR-192 in directly regulating KL levels, and through that, senescence and oxidative stress, key pathological processes in the development of DN. miR-192 and\/or KL levels are altered with severity and duration of diabetes and could serve as early biomarkers for DN.<\/jats:p>","DOI":"10.3389\/fendo.2022.937093","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T05:34:00Z","timestamp":1659677640000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Serum \u03b1-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhenwei","family":"Gong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro A. Pag\u00e1n","family":"Banchs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoyi","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent C.","family":"Arena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erick","family":"Forno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"Libman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radhika","family":"Muzumdar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"872193","DOI":"10.1155\/2015\/872193","article-title":"Soluble alpha -KL serum levels in chronic kidney disease","volume":"2015","author":"Rotondi","year":"2015","journal-title":"Int J Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-1710","article-title":"Prevalence of diabetes and diabetic nephropathy in a Large U.S. commercially insured pediatric population, 2002-2013","volume":"39","author":"Li","year":"2016","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5171945","DOI":"10.1155\/2018\/5171945","article-title":"The biological role of KL protein in the development of cardiovascular diseases","volume":"2018","author":"Olejnik","year":"2018","journal-title":"BioMed Res Int"},{"key":"B4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse KL gene leads to a syndrome resembling ageing","volume":"390","author":"Kuro-o","year":"1997","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1186\/s12882-018-1094-z","article-title":"The role of KL in chronic kidney disease","volume":"19","author":"Zou","year":"2018","journal-title":"BMC Nephrol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-154765","article-title":"KL: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule","volume":"24","author":"Hu","year":"2010","journal-title":"FASEB J Off Publ Fed Am Societies Exp Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1112766","article-title":"Suppression of aging in mice by the hormone KL","volume":"309","author":"Kurosu","year":"2005","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15280\/jlm.2015.5.1.1","article-title":"Biological role of anti-aging protein KL","volume":"5","author":"Kim","year":"2015","journal-title":"J lifestyle Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.4226","article-title":"Severely reduced production of KL in human chronic renal failure kidney","volume":"280","author":"Koh","year":"2001","journal-title":"Biochem Biophys Res Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3470","article-title":"In vivo KL gene delivery protects against endothelial dysfunction in multiple risk factor syndrome","volume":"276","author":"Saito","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611079104","article-title":"Amelioration of progressive renal injury by genetic manipulation of KL gene","volume":"104","author":"Haruna","year":"2007","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.328","article-title":"KL deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective","volume":"78","author":"Hu","year":"2010","journal-title":"Kidney Int"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009121311","article-title":"KL deficiency causes vascular calcification in chronic kidney disease","volume":"22","author":"Hu","year":"2011","journal-title":"J Am Soc Nephrol JASN"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.709564","article-title":"Soluble KL is decreased in children with type 1 diabetes and correlated with metabolic control","volume":"12","author":"Zubkiewicz-Kucharska","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611192104","article-title":"MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of e-box repressors","volume":"104","author":"Kato","year":"2007","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B16","doi-asserted-by":"publisher","first-page":"6954","DOI":"10.1038\/s41598-018-25295-x","article-title":"Reduced autophagy by a microRNA-mediated signaling cascade in diabetes-induced renal glomerular hypertrophy","volume":"8","author":"Deshpande","year":"2018","journal-title":"Sci Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011050485","article-title":"Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy","volume":"23","author":"Putta","year":"2012","journal-title":"J Am Soc Nephrol JASN"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0305","article-title":"Transforming growth factor-beta-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy","volume":"62","author":"Deshpande","year":"2013","journal-title":"Diabetes"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/jcm4071498","article-title":"Urinary MicroRNA profiling predicts the development of microalbuminuria in patients with type 1 diabetes","volume":"4","author":"Argyropoulos","year":"2015","journal-title":"J Clin Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12180","article-title":"ISPAD clinical practice consensus guidelines 2014. microvascular and macrovascular complications in children and adolescents","author":"Donaghue","year":"2014","journal-title":"Pediatr Diabetes"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.06.006","article-title":"Association of elevated urinary miR-126, miR-155, and miR-29b with diabetic kidney disease","volume":"188","author":"Beltrami","year":"2018","journal-title":"Am J Pathol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058014","article-title":"Increased circulating miR-21 levels are associated with kidney fibrosis","volume":"8","author":"Glowacki","year":"2013","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24020264","article-title":"MicroRNA-29a attenuates diabetic glomerular injury through modulating cannabinoid receptor 1 signaling","volume":"24","author":"Tung","year":"2019","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-010-1860-3","article-title":"In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh epidemiology of diabetes complications study","volume":"53","author":"Orchard","year":"2010","journal-title":"Diabetologia"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021835","article-title":"Regression of microalbuminuria in type 1 diabetes","volume":"348","author":"Perkins","year":"2003","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv121","article-title":"Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with type 1 diabetes","volume":"30","author":"Bjornstad","year":"2015","journal-title":"Nephrol Dial Transplant"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2841","article-title":"Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis","volume":"33","author":"Papadopoulou-Marketou","year":"2017","journal-title":"Diabetes Metab Res Rev"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4219-1","article-title":"Perturbations of the anti-ageing hormone KL in patients with type 1 diabetes and microalbuminuria","volume":"60","author":"Maltese","year":"2017","journal-title":"Diabetologia"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.902765","article-title":"Relationship of soluble KL and early stage of diabetic nephropathy: A systematic review and meta-analysis","volume":"13","author":"Xin","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B30","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.addr.2017.07.009","article-title":"Effects of KL on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies","volume":"121","author":"Mencke","year":"2017","journal-title":"Advanced Drug delivery Rev"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1262","article-title":"KL depletion contributes to increased inflammation in kidney of the db\/db mouse model of diabetes via RelA (serine)536 phosphorylation","volume":"60","author":"Zhao","year":"2011","journal-title":"Diabetes"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2018.9040","article-title":"Expression of microRNA377 and microRNA192 and their potential as bloodbased biomarkers for early detection of type 2 diabetic nephropathy","volume":"18","author":"Al-Kafaji","year":"2018","journal-title":"Mol Med Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010020134","article-title":"miR-192 mediates TGF-beta\/Smad3-driven renal fibrosis","volume":"21","author":"Chung","year":"2010","journal-title":"J Am Soc Nephrol JASN"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00294.2011","article-title":"Reduced KL expression level in kidney aggravates renal interstitial fibrosis","volume":"302","author":"Sugiura","year":"2012","journal-title":"Am J Physiol Renal Physiol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.937093\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T05:34:02Z","timestamp":1659677642000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.937093\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,5]]},"references-count":34,"alternative-id":["10.3389\/fendo.2022.937093"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.937093","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,5]]},"article-number":"937093"}}